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Altered thymic T-cell selection due to a mutation of the ZAP70 gene causes autoimmune arthritis in mice

Altered thymic T-cell selection due to a mutation of the ZAP70 gene causes autoimmune arthritis in mice,10.1038/nature02119,Nature,Noriko Sakaguchi,Ta

Altered thymic T-cell selection due to a mutation of the ZAP70 gene causes autoimmune arthritis in mice   (Citations: 195)
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Rheumatoid arthritis (RA), which afflicts about 1% of the world population, is a chronic systemic inflammatory disease of unknown aetiology that primarily affects the synovial membranes of multiple joints. Although CD4+ T cells seem to be the prime mediators of RA, it remains unclear how arthritogenic CD4+ T cells are generated and activated. Given that highly self-reactive T-cell clones are deleted during normal T-cell development in the thymus, abnormality in T-cell selection has been suspected as one cause of autoimmune disease. Here we show that a spontaneous point mutation of the gene encoding an SH2 domain of ZAP-70, a key signal transduction molecule in T cells, causes chronic autoimmune arthritis in mice that resembles human RA in many aspects. Altered signal transduction from T-cell antigen receptor through the aberrant ZAP-70 changes the thresholds of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might also be crucial to the development of disease in a subset of patients with RA.
Journal: Nature , vol. 426, no. 6965, pp. 454-460, 2003
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    • ...6 Indeed, as we will discuss, data emerging from mouse models indicate that distinct thresholds of signaling can give rise to specific disease phenotypes, due in part to the fact that the TCR is pleiotropic, delivering quantitatively distinct signals in different cell lineages, including effector and regulatory cells...

    Shimon Sakaguchiet al. T-cell receptor signaling and the pathogenesis of autoimmune arthritis...

    • ...Arthritis severity was evaluated according to the clinical arthritis scores as follows: 0, no joint swelling; 0.1, swelling of one finger joint; 0.5, mild swelling of wrist or ankle; 1.0, severe swelling of wrist or ankle, as previously reported [23]...

    Kenta Misakiet al. Histone deacetylase inhibition alters dendritic cells to assume a tole...

    • ...of spontaneous mutants from breeding colonies (for example, SKG mice with a point mutation in Zap-70 [36])...
    • ...Though visible swelling was most evident in the large distal joints of IIJ mice, histological hallmarks of arthritis, including bone and cartilage erosion, invasive synovial hyperproliferation and immune cell infiltration were observed in all joints of the hindlimbs and forelimbs (Figure 1). Overall, the histopathology was similar to that described in previously published mouse models of autoimmune arthritis [32,34-36]...
    • ...Elevation of serum proinflammatory cytokines (Figure 5) and histological signs of inflammation, ranging from mild to severe, were observed in various organs (Table 3). Extraarticular manifestations of disease have also been noted in IL-1R antagonist-deficient [50] and SKG mice [36]...
    • ...The sex bias appeared to be specific for the arthritis phenotype, since the incidence of typhlocolitis was similar between male and female IIJ mice (Table 4). As most models reach 100% incidence in both sexes, no other spontaneous mouse model of arthritis has found such a sex bias, although researchers who have studied both the SKG [36] and gp130 Y759F models [35] have noted more severe arthritis...

    Iris A Adipueet al. Characterization of a novel and spontaneous mouse model of inflammator...

    • ...is identified to cause chronic autoimmune arthritis in mice ...

    Hirofumi Nakaokaet al. A Systems Genetics Approach Provides a Bridge from Discovered Genetic ...

    • ... Runx1 binds in the DN3 compartment to sites present in the Cd4 silencer, and Ets-1 has been demonstrated to have an essential role in β-selection as well as allelic exclusio...

    Masaki Miyazakiet al. The opposing roles of the transcription factor E2A and its antagonist ...

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